Histogranin (HN, Scheme 1) (SEQ ID NO. 1), a pentadecapeptide whose structure presents 80% and 73% homologies with those of fragment-(86–100) of histone H4 (SEQ ID NO. 2) and osteogenic growth peptide (OGP) (SEQ ID NO. 3), respectively, was first isolated from extracts of bovine adrenal medulla (Lemaire, Eur. J. Pharmacol., 1993, 245, 247–256), a tissue recognized to contain various pain reducing substances, including the endogenous opioid peptides Met- and Leu-enkephalins and catecholamines (Boarder et al. J. Neurochem., 1982, 39, 149–154; Liston et al. Science, 1984, 225, 734–737).
I.c.v. administration of HN (SEQ ID NO. 1) and related peptides in mice dose-and structure-dependently blocked writhing induced by i.p. administration of acetic acid and tail-flick induced by radiant heat (Lemaire et al., Soc. Neurosci. 1997, 23, 674., Ruan, Prasad and Lemaire, Pharmcol. Biochem. Behav. 2000, 66, 1–9). In addition, [Ser1]HN, a chemically stable analog of HN (SEQ ID NO. 1) (Shukla and Lemaire, Pharmcol. Biochem. Behav. 1995, 50, 49–54), blocked tonic pain in the rat formalin assay (Siegen and Sagan, Neuroreport. 1997, 8 1379–81) and attenuated hyperalgesia and allodynia caused by sciatic nerve injury (Siegan and Sagen, Brain Res. 1997, 755, 331–334) and intrathecal (i.t.) administration of N-methyl-D-aspartate (NMDA; Hama and Sagen, Pharmacol. Biochem. Behav., 1999, 62, 67–74).
Scheme 1:
    Histogranin (HN) (SEQ ID NO. 1):    Met-Asn-Tyr-Ala-Leu-Lys-Gly-Gln-Gly-Arg-Thr-Leu-Tyr-Gly-Phe    H4-(86–100) (Histone H4 fragment) (SEQ ID NO. 2):    Val-Val-Tyr-Ala-Leu-Lys -Arg-Gln-Gly-Arg-Thr-Leu-Tyr-Gly-Phe    OGP (Osteogenic Growth Peptide) (SEQ ID NO. 3):    Ala-Leu-Lys-Arg-Gln-Gly-Arg-Thr-Leu-Tyr-Gly-Phe-Gly-Gly    Histogranin(7–15) (SEQ ID NO. 4):

In the mouse writhing tail-flick assays, the analgesic effects of i.c.v. administration of HN (SEQ ID NO. 1) and related peptides are not mediated by opioid receptors and may involve a participation of dopamine D2 sites (Ruan, Prasad and Lemaire, Pharmcol. Biochem. Behav. 2000, 66, 1–9). A hypothesis is that HN (SEQ ID NO. 1) and related peptides bind to a specific receptor present in the brain (Roger et Lemaire, J. Pharmacol. Exp. Ther., 1993, 267, 350–356) and on peripheral cells (Lemaire et al., Biochem Biophys Res Commun. 1993, 194, 1323–9) and modulate processes involved in the pathophysiology of pain.
Among various HN related peptides and fragments, the C-terminal peptide HN-(7–15) (SEQ ID NO. 1) (Scheme 1) was shown to be particularly potent in the mouse writhing test with an AD50 of 8.5 nmol/mouse as compared with 23 nmol/mouse for HN (SEQ ID NO. 1) (Ruan, Prasad and Lemaire, Pharmcol. Biochem. Behav. 2000, 66, 1–9; Canadian patent application 2,219,437).